Search Results (471)

(1) Background: The concentration of lamotrigine, an antiepileptic drug very often used in bipolar disorder, is most often determined in the blood, with many inconveniences. An alternative may be to use saliva as a diagnostic material for this purpose. The development of a method to determine lamotrigine in saliva as a biological material significantly improves patient comfort during sampling. The developed method uses solid-phase extraction for the isolation of the drug from saliva for the first time. (2) Methods: This study aimed to develop a method to determine lamotrigine in saliva using solid-phase extraction (SPE) for isolation and liquid chromatography with a diode array detector (LC-DAD) for quantitative analysis. (3) Results: The method was validated by determining its linearity in the concentration range 10–2000 ng/mL (R² > 0.99), and the intra- and inter-day precision expressed as coefficient of variation (CV%) did not exceed 15%. (4) Conclusions: The developed method was used to determine the salivary concentration of lamotrigine in patients treated with the studied compound, confirming its usefulness in bipolar disorder (BD). Full article

Background/Objectives: Epilepsy is a brain condition that affects millions of people worldwide. Although there are many antiepileptic drugs with different mechanisms of action, many patients still fail to control their agonizing symptoms, a situation that highlights the need for more strategies to address this issue. In this in vitro study, we elucidated and characterized the alterations in intracellular Ca²⁺ levels in cell cultures where diazepam and repetitive transcranial magnetic stimulation were implemented, alone or in combination. Methods: Using the differentiated human-derived neuroblastoma cell line SH-SY5Y, we measured the alterations in intracellular Ca²⁺ levels under the impact of either low-frequency repetitive transcranial magnetic stimulation (1 Hz), diazepam (14 μM), or their combination. We used the Ca²⁺-sensitive fluorescent indicator Fluo-4 acetoxymethyl ester for calcium imaging, while neuronal excitation was achieved with 50 mM KCl. Results: The highest median fluorescence intensity increase (%ΔF/F = 24.80) was observed in control cell cultures, followed by rTMS cultures (%ΔF/F = 16.96) and diazepam cultures (%ΔF/F = 11.46). The lowest median fluorescence intensity value (%ΔF/F =−0.44) was observed when diazepam was used concomitantly with repetitive transcranial magnetic stimulation. Post hoc analysis assessed pairwise differences, showing statistically significant differentiation between the control group and all other groups. Additionally, statistically significant results were observed between repetitive transcranial magnetic stimulation or diazepam and their combination, but not between them. Conclusions: The combination of diazepam and repetitive transcranial magnetic stimulation resulted in the most significant reduction in intracellular Ca²⁺ levels, as indicated by the lowest fluorescence values compared with the control group. Individually, each treatment produced a notable but less pronounced effect. We conclude that both diazepam and low-frequency repetitive transcranial magnetic stimulation can control epileptiform activity in vitro, while their combination is the most effective treatment. Full article

Objective: The interactions between the central nervous system (CNS) and the immune system suggest that immune mechanisms may be effective in the pathogenesis of epilepsy and epileptic seizures. Although studies on the natural immune response and epilepsy are continuing, it is not yet clear whether the interaction of the current immune system is due to epilepsy itself or antiepileptic drugs (AEDs), since epileptic patients also use AEDs There are a limited number of studies that have reported an increased incidence of upper respiratory tract infections (URTIs) in patients during levetiracetam (LEV) treatment. Therefore, we aimed to report our experience regarding the effect of LEV monotherapy on the complete blood count (CBC), immunoglobulin (Ig) levels, and lymphocyte subgroups in the interictal period in children and adolescents with epilepsy. Methods: This study enrolled 31 children who presented with epilepsy and underwent LEV monotherapy for at least one year (patient group) and 43 healthy children (control group). The CBC parameters (hemoglobin (hb), lymphocytes, leukocytes, neutrophils, and platelets), Ig levels (IgA, IgM, IgG, and IgE), and lymphocyte subsets (CD3, CD4, CD8, CD4/CD8 ratio, CD19, CD56, NKT cells, and Treg cells) were measured and compared between the two groups. The patients were also investigated regarding the frequency and types of infections that they experienced in the first month and first year of the study, and these data were compared between the patient group and the control group. In addition, the same parameters and the frequency of infection were compared among the patient subgroups (focal and generalized seizures). Results: The results of the present study indicate that there were no significant differences in the CBC parameters, lymphocyte subsets, or Ig levels between the patient group and the control group. The comparison among the patient subgroups was similar; however, the CD4/CD8 ratio was lower in the patient subgroup with focal seizures. In addition, there were no significant differences in the frequency or type of infections experienced one month and one year of the study between the patient group and the control group, and likewise for the patient subgroups (focal and generalized seizures). Conclusions: The present study demonstrated that LEV monotherapy did not increase the incidence of infection, and there were no significant effects on the CBC or on the humoral or cellular immune system in epileptic children. These findings also suggest that the CD4/CD8 ratio among lymphocyte subgroups is lower in patients with focal seizures. However, the epilepsy subgroups had a relatively small sample size; therefore, further prospective studies involving a larger patient population are needed to establish the association between LEV monotherapy and lymphocyte subgroups in patients with epilepsy. Full article

This review explores the potential of magistral formulas (MFs) as a viable option to meet the needs of neonates, given the lack of adequate therapies for this vulnerable group. The scientific literature on medicines available for neonates is limited. The physiological differences between neonates and adults make it difficult to formulate these medicines. In addition, there are a variety of difficulties in conducting research on neonates: few clinical trials are performed, and there is frequent use of unauthorized medicines. Pharmacokinetics in neonates was investigated in comparison to adults, and different aspects of the absorption, distribution, metabolism, and excretion were observed. One of the main problems is the different pharmacokinetics between the two populations. It is necessary to promote and allow research related to pediatric drug design, approve a specific authorization for use in age-appropriate dosage forms, and improve the quality and availability of information on drugs. This study focused on the MFs typically used for pediatrics, specifically for neonates, analyzing the pharmaceutical forms currently available and the presence of indications and dosage recommendations of the European Medicines Agency. Medications were classified according to therapeutic group, as antihypertensives, corticosteroids, and antiepileptics. The use of off-label medicines remains high in neonatal intensive care units and in primary healthcare, besides in the preparation of MFs by pharmacists. The shortage of medicines specifically designed and approved for neonates is a serious problem for society. Neonates continue to be treated, on numerous occasions, with off-label medicines. Studies and research should be expanded in this vulnerable population group. Full article

Background/Objectives: Epilepsy affects approximately 50 million people worldwide, with antiepileptic drugs (AEDs) remaining the cornerstone of treatment. Due to their narrow therapeutic windows, AEDs are ideal candidates for therapeutic drug monitoring (TDM). Oral fluid is increasingly considered a viable alternative to blood and urine, as it reflects the free (active) concentration of many AEDs. Its non-invasive collection, which does not require trained personnel, makes it particularly suitable for TDM in paediatric and geriatric populations. However, as samples are often stored for extended periods before analysis, analyte stability becomes a critical concern. This study aimed to evaluate the stability of four commonly used AEDs in dried saliva spot (DSS) samples. Methods: Phenobarbital, phenytoin, carbamazepine, and carbamazepine-10,11-epoxide were analysed in oral fluid samples collected via spitting and stored as DSSs. Quantification was performed using high-performance liquid chromatography with diode array detection (HPLC-DAD). Design of experiments tools were used to assess the effects of preservatives, storage temperatures, light exposure, and storage durations on analyte stability. Results: Optimal conditions were refrigeration in the dark, with a low concentration of ascorbic acid as preservative. Samples at 10 µg/mL remained stable for 14 days longer than those without preservative or reported in previous studies. Unexpectedly, at 0.5 µg/mL, analytes in samples without preservative showed greater stability. Conclusions: To our knowledge, this is the first study combining DSS and HPLC-DAD to assess the stability of these AEDs in oral fluid, providing valuable insights for non-invasive TDM strategies and supporting the feasibility of saliva-based monitoring in clinical settings. Full article

Temporal lobe epilepsy (TLE) is a common drug-resistant form of epilepsy, often accompanied by cognitive and emotional disturbances, highlighting the urgent need for novel therapies. Scorpion Venom Heat-Resistant Synthetic Peptide (SVHRSP), isolated and synthetically derived from scorpion venom, has shown anti-epileptic and neuroprotective potential. This study evaluated the anti-epileptic effects of SVHRSP in a kainic acid (KA)-induced TLE rat model. Our results demonstrated that SVHRSP (0.81 mg/kg/day) reduced the frequency and severity of spontaneous seizures. Behavioral tests showed improved cognitive performance in the novel object recognition, object location, and T-maze tasks, as well as reduced anxiety-like behavior in the open-field test. Moreover, SVHRSP mitigated hippocampal neuronal loss and glial activation. Transcriptomic analysis indicated that SVHRSP upregulates genes involved in adhesion molecule-triggered and axon guidance pathways. Western blotting and immunofluorescence further confirmed that SVHRSP restored dendritic (MAP2), axonal (NFL), and synaptic (PSD95) marker expression, elevated the functionally important L1CAM fragment (L1-70), and increased myelin basic protein-induced serine protease activity responsible for L1-70 generation. Blockade of L1CAM expression diminished the neuroprotective effects of SVHRSP, suggesting a critical role for L1CAM-mediated synapse functions. This study is the first to reveal the therapeutic potential of SVHRSP in TLE via L1CAM-associated mechanisms. Full article

Epilepsy remains a widespread neurological disorder, with approximately 30% of patients showing resistance to current antiepileptic therapies. To address this unmet need, a series of 2-(isoindolin-2-yl) esters derived from natural amino acids were designed and evaluated for their potential interaction with the GABA_A receptor. Sixteen derivatives were subjected to in silico assessments, including physicochemical and ADMET profiling, virtual screening–ensemble docking, and enhanced sampling molecular dynamics simulations (metadynamics calculations). Among these, compounds derived from the aromatic amino acids, phenylalanine, tyrosine, tryptophan, and histidine, exhibited superior predicted affinity, attributed to π–π stacking interactions at the benzodiazepine binding site of the GABA_A receptor. Based on computational performance, the tyrosine and tryptophan derivatives were synthesized and further assessed in vivo using the pentylenetetrazole-induced seizure model in zebrafish (Danio rerio). The tryptophan derivative produced comparable behavioral seizure reduction to the reference drug diazepam at the tested concentrations. The results implies that aromatic amino acid-derived isoindoline esters are promising anticonvulsant candidates and support the hypothesis that π–π interactions may play a critical role in modulating GABA_A receptor binding affinity. Full article

Backgrounds/Objectives: This study aims to comprehensively characterize the prevalence and severity of antiepileptic drug (AED)-induced adverse drug events (ADEs) and to identify predictors strongly associated with serious adverse events (SAEs) in both general and geriatric populations. Methods: This cross-sectional study investigated AED-related ADEs reported to the KIDS KAERS DB from January 2014 to December 2023. Disproportionality analysis was performed to detect the association between reported SAEs, and multiple logistic regression was conducted to identify predictors associated with SAEs. Cox’s proportional hazard model was utilized to assess ADE duration in elderly patients aged 60 years and older. Results: More than 50% of 36,809 AED-related ADEs were reported in elderly patients aged 60 years and older, and the prevalence of SAEs was 3.78%. ADEs associated with endocrine disorders had the highest likelihood of SAEs being reported (ROR 15.30), followed by hematological disorders. The predictors associated with elevated SAE risks in the elderly were male sex (OR 1.91; 95% CI 1.62–2.27), aging (OR 1.17; 95% CI 1.04–1.31), and certain AEDs. However, the concomitant administration of acid-suppressive therapy (AST) and opioids was associated with a lower risk of SAEs in the elderly population. Elderly patients not receiving concomitant AST were less likely to experience prolonged ADE duration (HR 0.28, 95% CI 0.07–1.15); however, no substantial differences in ADE duration were observed with the concomitant use of opioids. Conclusions: This study implies significant variability in the frequency, severity, and duration of ADEs depending on the type of AEDs, patient demographics, and concomitant medication use. Full article

Background/Objectives: Sudden unexpected death in epilepsy (SUDEP) is a major cause of mortality in pediatric epilepsy. Cardiac arrhythmias, possibly reflected by electrocardiographic (ECG) abnormalities, are thought to contribute significantly to SUDEP risk. This study aimed to evaluate ECG indices associated with an increased risk of both atrial and ventricular arrhythmias and sudden cardiac death in pediatric patients with generalized and focal seizures, excluding those with underlying channelopathies. Materials and Methods: Pediatric patients aged 0–18 years with generalized or focal epilepsy followed at our center between October 2024 and April 2025 were enrolled. Comprehensive cardiac evaluations, including echocardiography and 12-lead ECG, were conducted. Patients with channelopathies, structural heart defects, or significant congenital heart disease were excluded. ECG parameters—QT dispersion (QT Disp), corrected QT interval (QTc), QTc dispersion (QTc Disp), P-wave dispersion (P Disp), and T peak-T end interval (Tp-e)—were analyzed across epilepsy subgroups and compared to healthy controls. Effects of antiepileptic drug (AED) use and gender were also assessed. Results: A total of 151 participants were included (generalized: n = 51; focal: n = 50; controls: n = 50). QTc and Tp-e intervals were prolonged in both epilepsy groups compared to controls (p = 0.001 and p = 0.036, respectively), however, they fell within the conventional parameters. AED use was associated with further prolongation of QTc (p = 0.035) and Tp-e (p = 0.037), these metrics were similarly found to be within the established normative boundaries. Phenobarbital and lamotrigine users showed the longest QTc, albeit not statistically significant. Males with generalized seizures had longer maximum P-wave duration (P Max) than females (p = 0.009). A moderate correlation was found between Tp-e and QTc (r = 0.557, p = 0.001). Conclusions: Although there are findings in our study that may suggest a relationship between SUDEP and arrhythmia according to electrocardiographic markers associated with arrhythmia risk, larger and prospective studies with long-term follow-up are needed in the future. Full article

Background: The development of cerebral organoids created from human pluripotent stem cells in 3D culture may greatly improve the discovery of neuropsychiatric medicines. Methods: In the current study we differentiated neural organoids from a human pluripotent stem cell line in vitro, recorded the development of neurophysiological activity using multielectrode arrays (MEAs) and characterized the neuropharmacology of synaptic signaling over 8 months in vitro. In addition, we investigated the ability of these organoids to display epileptiform activity in response to a convulsant agent and the effects of antiseizure medicines to inhibit this abnormal activity. Results: Single and bursts of action potentials from individual neurons and network bursts were recorded on the MEA plates and significantly increased and became more complex from week 7 to week 30, consistent with neural network formation. Neural spiking was reduced by the Na channel blocker tetrodotoxin but increased by the inhibitor of K_V7 potassium channels XE991, confirming the involvement of voltage-gated sodium and potassium channels in action potential activity. The GABA antagonists bicuculline and picrotoxin each increased the spike rate, consistent with inhibitory synaptic signaling. In contrast, the glutamate receptor antagonist kynurenic acid inhibited the spike rate, consistent with excitatory synaptic transmission in the organoids. The convulsant 4-aminopyridine increased spiking, bursts and synchronized firing, consistent with epileptiform activity in vitro. The anticonvulsants carbamazepine, ethosuximide and diazepam each inhibited this epileptiform neural activity. Conclusions: Together, our data demonstrate that neural organoids form inhibitory and excitatory synaptic circuits, generate epileptiform activity in response to a convulsant agent and detect the antiseizure properties of diverse antiepileptic drugs, supporting their value in drug discovery. Full article

Zika virus (ZIKV), once considered a relatively benign pathogen, has emerged as a cause of severe neurological complications, including Guillain-Barrè Syndrome and encephalitis. This report presents the case of a 21-year-old Brazilian woman who initially presented with fever, rash, and arthralgia. Seven days later, she developed confusion, speech impairment, and gait disturbance. Following a tonic-clonic seizure, neurological examination revealed dysphonia, dysarthria and facial palsy, suggestive of brainstem involvement. ZIKV infection was detected by positive IgM serology and a plaque reduction neutralization test. The patient was treated with corticosteroids and antiepileptic drugs, leading to substantial clinical improvement, and discharge after 25 days of hospitalization. This case underscores the neuroinvasive potential of ZIKV and highlights the importance of early recognition and management of atypical neurological manifestations. It also reinforces the need to consider ZIKV in the differential diagnosis of encephalitis, particularly in endemic regions, and contributes to the growing understanding of ZIKV neurotropism and possible therapeutic approaches for severe presentations. Full article

Background: Developmental epileptic encephalopathies (DEEs) are often associated with variably severe cognitive and motor impairment and frequent refractory epilepsy, with many children not achieving adequate seizure control via standard antiepileptic medications. The classic ketogenic diet (KD) has proven effective in reducing seizure frequency and/or severity in a category of DEEs and in certain refractory epilepsies of infancy. However, its multifaceted mechanisms, e.g., epigenetic modulation, anti-inflammatory and antioxidative effects, and direct neuronal excitability changes, are balanced by a high burden and low long-term adherence. Medium-chain triglycerides (MCTs), particularly decanoic acid (C10:0), have gained attention in recent years for their potential direct inhibitory action on AMPA receptors, contributing to seizure reduction. Methods: A systematic review was conducted, including articles from January 2000 to January 2025, to explore the potential role of medium-chain triglyceride (MCT) add-on to classic KD and as MCT supplementation in free diets in the management of pediatric drug-resistant epilepsy (DRE). Results: Selected studies show how the action of MCTs, and decanoic acid in particular, is via negative modulation of AMPA receptors, with a positive impact on epileptic seizures. Conclusions: This review discusses the complexities of implementing and sustaining KD in children and presents recent pre-clinical and clinical evidence, including trials where MCTs (often enriched in decanoic acid) serve as an add-on therapy in both ketogenic and free/unrestricted diets. The summarized findings reinforce the therapeutic potential of MCTs, highlighting both the beneficial seizure outcomes and the hurdles that remain to be addressed through future research. Full article

Objectives: Drug–drug cocrystallization represents a promising approach for the development of novel combination drugs with improved physicochemical and biopharmaceutical properties. The aim of the present research is to prepare novel drug-drug cocrystalline forms of antiepileptic drug carbamazepine (CBZ) with sulfacetamide (SCTM). Methods: The novel CBZ cocrystal methanol solvate and cocrystal hydrate were prepared via solvent evaporation technique and characterized by single crystal X-ray diffraction, differential scanning calorimetry and thermogravimetric analysis. Results: Single-crystal X-ray diffraction and thermal analysis revealed that the multicomponent solids are isostructural, wherein the solvent molecule does not play a structure-forming role. To optimize the synthesis of [CBZ+SCTM+H₂O] (1:1:0.7), the binary and ternary phase diagrams were constructed in acetonitrile at 25 °C. A thorough investigation of the cocrystal hydrate behavior in aqueous solution showed that the pH of the dissolution medium exerted a significant effect on the stability and solubility of [CBZ+SCTM+H₂O] (1:1:0.7). According to the dissolution and diffusion experiments in a buffer solution pH 6.5, the cocrystal hydrate characterized an enhanced dissolution rate and flux of CBZ. Pharmacokinetic studies in rabbits showed that the novel cocrystal hydrate exhibited a comparable bioavailability to the parent CBZ. Conclusions: Overall, this work reports the preparation of a novel CBZ drug-drug cocrystal hydrate, which can be considered as an alternative CBZ solid form for oral usage, possessing additive pharmacological effect. Full article

Background: It has been demonstrated that levetiracetam can decrease absence epileptic activity in both human patients and different types of animal models of absence epilepsy, such as the genetically absence epileptic Wistar Albino Glaxo/Rijswijk (WAG/Rij) rat. It was also suggested previously that exogenous ketone supplements (EKSs)-evoked ketosis not only decreases the number of spike-wave discharges (SWDs) but also enhances the anti-absence epileptic effect of pyrimidine nucleoside uridine in WAG/Rij rats. These findings suggest that EKSs may enhance the efficacy of clinically used anti-epileptic drugs, such as levetiracetam. Methods: We investigated the effect of not only levetiracetam (intraperitoneal/i.p. 200 mg/kg) alone and KEKS supplemented food (containing 10% ketone ester/KE and 10% ketone salt/KS in a normal rat chow) alone, but also the combination of levetiracetam and KEKS supplemented food on SWD number and SWD time for 5 days in WAG/Rij rats. For evaluation of SWDs, electroencephalographic (EEG) recordings were performed every day. Moreover, for the measurement of blood glucose and R-beta-hydroxybutyrate (R-βHB) levels, the blood was taken from the tail vein of rats after EEG registration. Results: It was demonstrated that the administration of both levetiracetam alone and KEKS food alone decreased the SWD number and time spent in SWD, compared to control. Moreover, after combined administration of levetiracetam with KEKS food, enhanced anti-absence epileptic effect was observed, compared to levetiracetam alone. Blood R-βHB level significantly increased after administration of both KEKS food alone and KEKS food in combination with levetiracetam. Nevertheless, these treatments did not significantly change the blood glucose levels. Conclusions: We can conclude that EKSs may be able to enhance the anti-epileptic effect of different drugs, and this combined treatment method may represent a promising new approach and effective therapy against epileptic seizures, especially in treatment-resistant patients. Full article

Background: The two antiepileptic drugs lacosamide and lamotrigine exert their antiepileptic effect by inhibiting sodium channels. Lacosamide enhances the inactivation of sodium channels, while lamotrigine inhibits the activation of the channel. Interactions with sodium channels also play an interesting role in cardiac pro- and antiarrhythmia, with inhibition of inactivation, in particular, being regarded as potentially proarrhythmic. Therefore, the ventricular electrophysiologic effects of lacosamide and lamotrigine were investigated in an established experimental whole-heart model. Methods: A total of 67 rabbit hearts were allocated to four groups. Retrograde aortic perfusion was performed using the Langendorff setup. The action potential duration at 90% repolarization (APD₉₀), QT intervals, spatial dispersion of repolarization, effective refractory period, post-repolarization refractoriness, and VT incidence were determined. The electrophysiological effects of lacosamide and lamotrigine were investigated in increasing concentrations on the natively perfused heart. On the other hand, perfusion with the I_Kr-blocker sotalol was performed to increase arrhythmia susceptibility, followed by perfusion with lacosamide or lamotrigine to investigate the effects of both in a setting of increased arrhythmia susceptibility. Perfusion with lacosamide and lamotrigine tended to decrease APD₉₀ and QT-interval. As expected, perfusion with sotalol led to a significant increase in APD₉₀, QT interval, and arrhythmia incidence. Additive perfusion with lacosamide led to a further increase in arrhythmia incidence, while additive perfusion with lamotrigine led to a decrease in VT incidence. Conclusions: In this model, lacosamide showed proarrhythmic effects, especially in the setting of an additive prolonged QT interval. Lamotrigine showed no significant proarrhythmia under baseline conditions and rather antiarrhythmic effects with additive QT prolongation. Full article